Biological Amyloid Aggregation as a Post-Translational Regulatory Pathway

点击翻译按钮获取中文摘要

Under normal environmental situations, biological molecules perform the basic tasks necessary to maintain human cells. However, exposure to harsh and stressful conditions, such as high temperature, acidity, and UV radiation, can disrupt the function of these biological molecules and damage cellular components. This requires the activation of repair pathways, which attempt to compensate for the harmful effects of an environmental stressor. The success or failure of these cellular countermeasures ultimately determines whether a cell and/or organism survives exposure. Recently, we identified a new biological pathway that enhances survival during periods of cellular stress. Through the reversible formation of dense, insoluble, and fibrous protein clumps (termed amyloids) a cell can rapidly shut down non-essential functions, to focus on repairing the damaged components. What is particularly striking about these biological amyloids is their close resemblance to the toxic plaques found in patients with neurological disorders (such as Alzheimer's, Parkinson's and mad cow diseases). This suggests that this natural pathway may be one of the first examples of a biological counterpart to the disease-associated plaques. The goal of this research program is to enhance our understanding of this newly discovered biological phenomenon. How natural amyloid aggregates form and disassemble, what environmental stressors activate this process, and why it is protective to the cell are long-term questions that we hope to address. Specifically in the next 5 years, we will focus our efforts on the following three aims.***Aim I: Examine the essential role of a poorly understood family of biological molecules (noncoding RNA) in the formation of protein clumps. Here, we will identify how environmental signals activate these noncoding RNAs and how these active molecules convert proteins into amyloid aggregates.***Aim II: Find new environmental stressors that trigger amyloid formation. This will help us understand how often cells/organisms utilize this novel stress-response pathway.***Aim III: Identify the proteins that form stress-specific amyloid aggregates. This is an important question, as it helps us understand how cells adapt to different situations (i.e., high temperature versus low pH), and the results will give us a better understanding of cellular pathways that enhance survival.***Overall, this work will be important to basic scientific communities (RNA, structural, and cellular biology), as well as translational researchers who could use our insight into the natural formation of amyloids to generate new therapeutic avenues that could help treat neurological diseases affecting Canada's aging population.**